Heterogeneous catalysis: Ni/C-catalyzed cross-couplings en route to allylated aromatics: Application to a precursor to coenzyme Q10

Article abstract of DOI:10.1055/s-2002-34384

The readily available, heterogeneous, and inexpensive catalyst nickel-on-charcoal (Ni/C) can be used to mediate couplings between vinyl alanes and benzylic chlorides under very mild conditions and in good yields. Although such allylated aromatics are them

Full text of DOI:10.1055/s-2002-34384

2110
PAPER
Heterogeneous Catalysis: Ni/C-Catalyzed Cross-Couplings en route to
Allylated Aromatics: Application to a Precursor to Coenzyme Q10
Cross-Couplings
r
with
H
et
u
erogeneous
c
N
i/C Cataly
e
st H. Lipshutz,* Bryan Frieman, Steven S. Pfeiffer
Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA 93106, USA
Fax +1(805)8938265; E-mail: lipshutz@chem.ucsb.edu
Received 14 June 2002
Warmly dedicated to Professor Dieter Seebach on the occasion of his retirement from the ETH.
Abstract: The readily available, heterogeneous, and inexpensive
catalyst nickel-on-charcoal (Ni/C) can be used to mediate couplings
between vinyl alanes and benzylic chlorides under very mild condi-
tions and in good yields. Although such allylated aromatics are
Scheme 2
themselves important compounds, as demonstrated in this work,
their syntheses under the ‘green chemistry’ conditions used can
smoothly arrive at precursors to valued quinone natural products,
such as the nutraceutical coenzyme Q10.
amounts of readily available and inexpensive nickel-on-
charcoal (Ni/C) (Scheme 2).
Key words: heterogeneous catalysis, nickel-on-charcoal, cross-
couplings, allylated aromatics, coenzyme Q10
Previously, we have described several Ni/C-catalyzed re-
actions (e.g., Negishi,4a Kumada,4b Suzuki,4c amina-
tions,4d reductions4e), all of which required reaction
temperatures close to or at the reflux point of the medium.
For the vinyl alanes used in this study, prepared in stan-
dard fashion by carboalumination of their precursor termi-
nal alkynes (1.2 equiv Me3Al, 0.25 equiv Cp2ZrCl2, 1,2-
dichloroethane, r.t.),5 it was therefore unexpected to find
that allylated aromatics could be formed cleanly at ambi-
ent temperatures. The general procedure arrived at relies
on 5 mol% Ni/C as catalyst, prepared from Ni(II)/C by
simple pre-treatment with 10 mol% BuLi in THF at 25 °C
for 5 minutes.6 Introduction of the vinyl alane followed by
the chloromethylated aromatic leads to efficient C–C
bond formation. Representative examples are illustrated
in Table 1.
In a recent report from these laboratories, an especially ef-
ficient synthesis of coenzyme Q10 (CoQ10; ubiquinone)
was disclosed.1 The key coupling reaction which accom-
plishes a net attachment of the 50 carbon side-chain to the
presursor to the p-quinone head group was effected in a
convergent, one-pot sequence.2 The ingredients combined
in this process included the benzylic chloride 1 and vinyl-
ic alane 2, the latter species derived in situ from alkyne 3
via carboalumination (Scheme 1).
The catalyst behind the success of this strategy is a nick-
el(0) complex generated from NiCl2(Ph3P)2 in the pres-
ence of n-BuLi (2 equiv). When used at the 3 mole percent
level in THF at room temperature, the CoQ10 skeleton was
produced in close to 90% isolated overall yield.1 In look-
ing for ways to alter the process so as to make it even more
environmentally benign as well as potentially more eco-
nomically attractive, use of Ni(0) impregnated onto a sol-
id support was considered.3 A heterogeneous alternative
might offer a simplified (non-aqueous) workup, as well as
opportunities for recycling of the catalyst. In this contri-
bution we present our preliminary work on the develop-
ment of cross-couplings between various benzylic
chlorides and vinylic alanes mediated by catalytic
In general, these data suggest that (1) reactions go to com-
pletion in reasonable times without resorting to unusually
high concentrations (ca. 0.25–0.30 M); (2) both electron-
rich and electron-poor substrates react with all-hydrocar-
bon-derived or -functionalized vinyl alanes at roughly
comparable rates; and (3) isolated yields tend to be quite
good. One heteroaromatic case studied, thiazole 4, did not
require any procedural changes en route to allylated prod-
uct 5 (Scheme 3).
O
MeO
MeO
MeO
MeO
+
1
+
Me2Al
H
H
Cl
9
H
9
10
O
TsO
CoQ10
3
1
2
Scheme 1
Synthesis 2002, No. 14, Print: 07 10 2002.
Art Id.1437-210X,E;2002,0,14,2110,2116,ftx,en;C03102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Cross-Couplings with Heterogeneous Ni/C Catalyst
2111
Table 1 Ni(0)/C-Catalyzed Couplings of Benzylic Chlorides with Vinylic Alanes
Entry
Chloride
Vinyl Alanea
Time (h)
Productb
Yield (%)c
C6H13
Cl
1
4
94
90
F
6
11
F
Cl
OTBDMS
Me2Al
Me2Al
Cl
2
17
12
OTIPS
Cl
OTIPS
3
4
5
9
10
13
84
91
78
F
6
14
F
Cl
OTBDMS
OTBDMS
OTIPS
Me2Al
Me2Al
CF3
CF3
15
16
Cl
OTIPS
OMe
OMe
Cl
Cl
Me2Al
Me2Al
Cl
6
7
10
16
87
84
12
OEt
OEt
C6H13
Cl
C6H13
OMe
OMe
18
a Formed via standard Cp2ZrCl2-catalyzed carboalumination conditions.
b Fully characterized by IR, NMR, MS, and HRMS data.
c Isolated, chromatographically purified material.
A disubstituted allylated aromatic of E-configuration Fortunately, this carboalumination/Ni(0)-catalyzed pro-
could also be constructed, in this case relying on an initial cess could be applied to the fully adorned CoQ10 nucleus.
hydrozirconation followed by transmetalation to the cor- Thus, following the usual protocol, the pentasubstituted
responding vinyl alane 7 (Scheme 4). Treatment of 7 with benzylic chloride 1 could be coupled with the 49 carbon
benzylic chloride 6 under the influence of Ni(0)/C at room vinyl alane side-chain 2 to arrive at the decaprenoid prod-
temperature led to 8 in 88% overall isolated yield.
cat Ni(0)/C
N
S
Cl
N
Me2Al
OTBDMS
+
OTBDMS
THF, rt, 17 h
S
5 (83%)
4
cat Cp2ZrCl2
Me3Al
OTBDMS
Scheme 3
Synthesis 2002, No. 14, 2110–2116 ISSN 0039-7881 © Thieme Stuttgart · New York

2112
B. H. Lipshutz et al.
PAPER
F
F
H
cat Ni(0)/C
+
Et2Al
Cl
THF, rt, 16 h
8 (88%)
6
7
1. Cp2Zr(H)Cl
2. Et2AlCl
Scheme 4
MeO
MeO
MeO
MeO
cat Ni(0)/C
+
Cl
Me2Al
H
9
H
THF, rt, 14 h
OTs
OTs
9
9
(85%)
1
2
Scheme 5
uct 9 in 85% yield after workup (i.e., filtration) and pas- tion solution was then removed and after solvent evapora-
sage through a short plug of silica gel (Scheme 5).
tion in vacuo, the product was purified to afford 11, again
in high yield (Scheme 7). The Ni/C left behind was re-
charged with additional vinyl alane and a different halide
[3-chlorobenzyl chloride (12)]. Thus, without reactivation
of the catalyst, this second cross-coupling proceded to
completion at room temperature in the expected time-
frame (cf. Table 1, entry 2). Isolation led to the newly cou-
pled product 13 in good yield. Thus, the inexpensive
catalyst Ni/C does not lose significant activity over (at
least) two consecutive independent cross-couplings, obvi-
ating reactivation by preliminary treatment with addition-
al BuLi.
The potential for recycling of Ni/C in these ambient tem-
perature couplings was tested in the case of 4-fluoroben-
zyl chloride (6; Table 1, entry 1). After the initial reaction
with alane 10 was complete, the catalyst was filtered and
then dried at 100 °C under vacuum for six hours. Reacti-
vation of the Ni/C (i.e., by treatment with BuLi) and sub-
sequent re-exposure to the identical reaction conditions
led to complete consumption of educt and afforded the ex-
pected product 11 in essentially the same yield
(Scheme 6).
To simplify the procedure further, the coupling above
(Scheme 6) was repeated with fresh reagents, and upon
complete consumption of p-fluorobenzyl chloride, the
mixture was centrifuged to settle the charcoal. The reac-
Analysis of the extent of nickel bleed from the charcoal
into solution was determined by ICP AES (inductively
coupled plasma atomic emission spectroscopy)7 on a
crude reaction mixture. Filtration of a Ni/C-catalyzed re-
F
F
cat Ni(0)/C
+
Et2Al
Cl
THF, rt, 4 h
6
10
11
1st use of Ni/C: 94%
nd use of Ni/C: 92%
1-octyne
2
Scheme 6
F
F
cat Ni(0)/C
THF, rt, 4 h
+
Et2Al
Cl
6
10
11
separate
1st use of Ni/C: 92%
&
re-use
Cl
Cl
cat Ni(0)/C
+
Et2Al
OTBDMS
Cl
OTBDMS
THF, rt, 16 h
13
12
2nd use of Ni/C: 88%
Scheme 7
Synthesis 2002, No. 14, 2110–2116 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cross-Couplings with Heterogeneous Ni/C Catalyst
2113
avoid contamination by the zirconium salts), and the hexanes were
removed in vacuo. The yellow hexanes solution was concentrated
under reduced pressure and the residue dissolved in THF (2 mL).
action between the vinyl alane from oct-1-yne and 3-
CF3C6H4CH2-Cl led to the observation that 0.24% of the
5% Ni/C (i.e., 2.359 ppm) had been released from the sol-
id support. This value is very much in line with those ob-
served previously4 for completed reactions run at reflux
that had been first cooled to room temperature, then fil-
tered, and ultimately digested using aqua regia. In our re-
cent study on the nature of Ni/C,8 it was shown that
couplings are taking place within the charcoal matrix but
are mediated by free nickel in solvent therein. Thus, it ap-
pears that elevated temperatures are clearly not required
(at least in this situation) in order to enhance the rate at
which coupling partners enter into, or product exits from,
the pores of the solid support.
Nickel-on-Charcoal Catalyzed Coupling: To a 10 mL round bottom
flask was added Ni/C (67.3 mg, 0.04 mmol) and Ph3P (21 mg, 0.08
mmol) under argon at r.t. THF (1 mL) was added followed by BuLi
(31 L, 2.55 M in hexanes, 0.08 mmol). The solution was allowed
to stir at r.t. for 5 min. The vinylalane was then transferred via can-
nula to the Ni/C catalyst at r.t. 4-Fluorobenzyl chloride (6; 96 L,
0.80 mmol) was added at r.t., and the cross-coupling reaction was
followed by GC analysis. When the reaction was complete (usually
<4 h), the solution was diluted with Et2O (10 mL) and quenched at
0 °C by carefully adding 1 M HCl dropwise (3 mL). The mixture
was filtered and the aq layer was extracted with Et2O ( 3 10 mL ).
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo. Silica gel column chromatography afforded product 11 as
a clear viscous oil (176 mg, 94%).
In summary, it has been demonstrated that nickel-on-char-
coal in the presumed Ni(0) state is a viable, efficient, and
‘green’ catalyst for effecting allylations of aromatic rings.
Couplings between vinylic alanes and chloromethylated
aromatics occur under mild conditions and in good yields.
The potential for this general process to be applied to the
synthesis of an established coenzyme Q10 precursor has
also been successfully documented. Further studies and
applications on this and related catalyst systems will be
reported in due course.
tert-Butyl{[(E)-7-(2-chlorophenyl)-5-methylhept-5-enyl]oxy}-
dimethylsilane (13)
The TBDMS protected hex-5-yn-1-ol (184 mg, 1 mmol), Me3Al
(1.5 mL, 3.0 mmol, 2 M in hexanes), Cp2ZrCl2 (146 mg, 0.50
mmol), and ClCH2CH2Cl (1 mL) were used in the carboalumination
following the procedure above with the exception that the carboalu-
mination was allowed to stir at r.t. for 6 h. Ph3P (21 mg, 0.08 mmol),
BuLi (33 L, 2.45 M), THF (1 mL), and 1-chloro-2-(chlorometh-
yl)benzene (12; 100 L, 129 mg, 0.8 mmol) were used in the cross-
coupling reaction following the typical procedure above. The reac-
tion was allowed to stir at r.t, for 17 h. Upon typical aqueous acidic
quench, chromatography of the residue on silica gel with 2%
CH2Cl2–petroleum ether afforded 253 mg of the title compound
(90%) as a clear oil; (2% CH2Cl2–petroleum ether).
Reactions were performed in oven-dried glassware under argon
with Teflon coated stir bars and dry septa. THF was freshly distilled
from Na/benzophenone ketyl prior to use. Hexanes and pentane
were freshly distilled from CaH2 prior to use. Ni/C was stored and
weighed out as a black powder in a glove box. All commercially
available reagents were distilled either from CaH2 or molecular
sieves under an inert atmosphere before use. Oct-1-yne, hex-5-yn-
1-ol, 6-chlorohex-1-yne, 4-fluorobenzyl chloride (6), 3-(trifluorom-
ethyl)benzyl chloride, and 3-methoxybenzyl chloride were pur-
chased from Aldrich. 4-Chloromethylthiazole hydrochloride was
purchased from Lancaster, and converted to the free-base with Et3N
and CH2Cl2. Petroleum ether used had bp 35–60 °C. Column chro-
matography was performed using Davisil Grade 633 Type 60A sil-
ica gel. TLC analysis was performed on commercial Kieselgel 60
IR (neat): 2930, 2858, 1654, 1468, 1254, 1101, 837 cm–1.
1H NMR (400 MHz, CDCl3): =7.34 (dd, J = 1.6, 7.8 Hz, 1 H),
7.25–7.10 (m, 3 H), 5.29 (tq, J = 0.8, 7.2 Hz, 1 H), 3.62 (t, J = 6.4
Hz, 2 H), 3.45 (d, J = 7.2 Hz, 2 H), 2.06 (t, J = 7.2 Hz, 3 H), 1.71
(s, 3 H), 1.52–1.45 (m, 4 H), 0.9 (s, 9 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3) = 136.45, 137.54, 135.25, 130.13,
129.52, 127.32, 126.92, 121.35, 63.35, 39.62, 32.64, 32.15, 26.20,
24.29, 18.60, –5.03.
MS (EI): m/z (%) = 295 (60, M – C4H9), 143 (18), 129 (22), 125
(29), 115 (18), 75 (100).
F
254 silica gel plates. NMR spectra were obtained on Varian Inova
HRMS (EI): m/z calcd for C20H33ClOSi (M – C4H9) 295.1285;
found 295.1287.
systems using CDCl3 or CD3CN solvents with proton and carbon
resonance at 400 MHz and 100 MHz, respectively. FTIR spectra
were obtained on an ATI Mattson Infinity series spectrometer neat
on NaCl plates, and are reported in cm–1. Mass spectral data were
acquired on a VF Autospec or an analytical VG-70-250 HF instru-
ment.
{[(E)-7-(4-Fluorophenyl)-5-methylhept-5-enyl]oxy}(triisopro-
pyl)silane (14)
TIPS-protected hex-5-yn-1-ol (190.6 L, 254 mg, 1 mmol), Me3Al
(1.50 mL, 3 mmol, 2 M in hexanes), Cp2ZrCl2 (146 mg, 0.5 mmol),
and ClCH2CH2Cl (1 mL) were used in the carboalumination follow-
ing the procedure above with the exception that the carboalumina-
tion was allowed to stir at r.t. for 3 h. Ni/C (58.9 mg, 0.035 mmol),
Ph3P (18.3 mg, 0.07 mmol), BuLi (26 L, 0.07 mmol, 2.70 M), THF
(1 mL), and 4-fluorobenzyl chloride (6; 83.8 L, 101 mg, 0.7 mmol)
were used in the cross coupling reaction following the procedure
above. The reaction was allowed to stir at r.t. for 9 h. Chromatogra-
phy of the residue on silica gel with hexanes afforded 222 mg of the
title compound 15 (84%) as a clear oil; Rf 0.13 (hexanes).
1-Fluoro-4-[(E)-3-methylnon-2-enyl]benzene (11); Typical Pro-
cedure
Carboalumination: To a 10 mL round-bottom flask under argon
was added Cp2ZrCl2 (73 mg, 0.25 mmol). A solution of Me3Al (0.75
mL, 2.0 M in hexanes, 1.5 mmol) was added at 0 °C via syringe and
the solution stirred under reduced pressure until the hexanes were
removed. ClCH2CH2Cl was added (1 mL) and the solution was al-
lowed to stir and warm to r.t. over 10 min. To this solution was add-
ed oct-1-yne (147.5 L, 1 mmol) and the mixture was stirred at 0 °C
for 30 min, after which time carboalumination was complete (as de-
termined by GC). The solvent was removed in vacuo and freshly
distilled hexanes (2 mL) were added and then also removed in vac-
uo. Additional hexanes (5 mL) were then added to the flask so as to
precipitate the zirconium salts. The vinylalane in hexanes was then
transferred to a second flask via cannula (with great care taken to
IR (neat): 2938, 2865, 1508, 1462, 1221, 1107, 882 cm–1.
1H NMR (400 MHz, CDCl3): = 7.37–7.30 (m, 1 H), 7.15–7.11 (m,
1 H), 6.98–6.94 (m, 2 H), 5.31 (tq, J = 1.2, 16.3 Hz, 1 H), 3.70 (t,
J = 6.1 Hz, 2 H), 3.33 (d, J = 7.4 Hz, 2 H), 2.07 (t, J = 7.1 Hz, 2 H),
1.70 (s, 3 H), 1.57–1.50 (m, 4 H), 1.07–1.06 (m, 21 H).
Synthesis 2002, No. 14, 2110–2116 ISSN 0039-7881 © Thieme Stuttgart · New York

2114
B. H. Lipshutz et al.
PAPER
1-Chloro-2-[(E)-7-chloro-3-methylhept-2-enyl]benzene (17)
13C NMR (100 MHz, CDCl3): = 136.49, 134.02, 128.72, 128.66,
123.01, 115.27, 112.88, 63.50, 39.59, 33.55, 32.80, 24.31, 18.27,
16.18, 12.23.
6-Chlorohex-1-yne (120 L, 1.0 mmol), Me3Al (0.75 mL, 1.50
mmol, 2 M in hexanes), Cp2ZrCl2 (73 mg, 0.25 mmol), and
ClCH2CH2Cl (1.0 mL) were used in the carboalumination following
the procedure above with the exception that the carboalumination
was allowed to stir at r.t. for 3 h. Ni/C (67.3 mg, 0.04 mmol), Ph3P
(21 mg, 0.08 mmol), BuLi (32 L, 0.08 mmol, 2.45 M), THF (1
mL), and 1-chloro-2-(chloromethyl)benzene (12; 100 mg, 0.80
mmol), dissolved in THF (0.5 mL) were used in the cross-coupling
reaction following the procedure above with the exception that pen-
tane was used to crash out the zirconocene salts instead of hexanes.
The reaction was allowed to stir at r.t. for 10 h. Chromatography of
the residue (5% CH2Cl2–petroleum ether) afforded 177.8 mg of the
title compound 17 (87%) as a clear oil; Rf 0.58 (5% CH2Cl2–petro-
leum ether).
MS (EI): m/z (%) = 335 (100, M – 43), 239 (5), 161 (10), 149 (29),
131 (49), 109 (80)
HRMS (EI): m/z calcd for C23H39FOSi, M+ 335.2216; found
335.2206.
tert-Butyl(dimethyl)({(E)-5-methyl-7-[3-(trifluoromethyl)phe-
nyl]hept-5-enyl}oxy)silane (15)
TBDMS-protected hex-5-yn-1-ol (297 L, 212 mg, 1 mmol),
Me3Al (1.50 mL, 3 mmol, 2 M in hexanes), Cp2ZrCl2 (146 mg, 0.5
mmol), and ClCH2CH2Cl (1 mL) were used in the carboalumination
following the procedure above with the exception that the carboalu-
mination was allowed to stir at r.t. for 5 h. Ni/C (58.9 mg, 0.035
mmol), Ph3P (18.3 mg, 0.07 mmol), BuLi (26 L, 0.07 mmol, 2.70
M), THF (1 mL), and 3-(trifluoromethyl)benzyl chloride (108.6 L,
136 mg, 0.7 mmol) were used in the cross coupling reaction follow-
ing the procedure above. The reaction was allowed to stir at r.t. for
10 h. Chromatography of the residue on silica gel using hexanes af-
forded 234 mg of the title compound 16 (91%) as a clear oil; Rf 0.13
(hexanes).
IR (neat): 2932, 2860, 1470, 1442, 1049, 750 cm–1.
1H NMR (400 MHz, CDCl3): = 7.35 (dd, J = 1.2, 7.6 Hz, 2 H),
7.24–7.12 (m, 3 H), 5.31 (tq, J = 1.2, 7.2 Hz, 1 H), 3.56 (t, J = 6.4
Hz, 2 H), 3.46 (d, J = 7.2 Hz, 2 H), 2.08 (t, J = 7.2 Hz, 2 H), 1.81–
1.72 (m, 5 H), 1.63–1.50 (m, 2 H).
13C NMR (100 MHz, CDCl3): = 139.30, 136.77, 134.16, 130.15,
129.56, 127.42, 126.97, 121.95, 45.28, 39.02, 32.31, 32.22, 25.21,
16.24.
IR (neat): 2930, 1331, 1256, 1164, 1128, 836, 775, 702 cm–1.
1H NMR (400 MHz, CDCl3): = 7.21–7.19 (m, 1 H), 6.81–6.74 (m,
3 H), 5.34 (tq, J = 1.2, 7.1 Hz, 1 H), 3.62 (t, J = 6.1 Hz, 2 H), 3.34
(d, J = 7.4 Hz, 2 H), 2.05 (t, J = 7.1 Hz, 2 H), 1.70 (s, 3 H), 1.59–
1.39 (m, 4 H), 0.90 (s, 9 H), 0.05 (s, 6 H).
MS (EI): m/z (%) = 256 (16, M+), 167 (34), 166 (12), 165 (100), 138
(25), 129 (23), 125 (35), 69 (34), 57 (33), 43 (33).
HRMS (EI): m/z calcd C14H18Cl2 256.0786; found 256.0785.
13C NMR (100 MHz, CDCl3): = 142.91, 137.68, 131.91, 128.90,
125.22, 125.18, 122.80, 122.77, 122.13, 63.27, 39.56, 34.15, 32.60,
26.17, 24.26, 18.58, 16.25, –5.08.
1-Ethoxy-4-methoxy-2-methyl-3-[(E)-3-methylnon-2-enyl]-
naphthalene (18)
Oct-1-yne (75 L, 0.5 mmol), Me3Al (0.38 mL, 0.75 mmol, 2 M in
hexanes), Cp2ZrCl2 (37 mg, 0.12 mmol), and ClCH2CH2Cl (0.5 mL)
were used in the carboalumination following the procedure above
with the exception that the carboalumination was allowed to stir at
r.t. for 1 h. Ni/C (33.7 mg, 0.02 mmol), Ph3P (10.5 mg, 0.04 mmol),
BuLi (16 L, 0.04 mmol, 2.45M), THF (1 mL), and 2-chlorometh-
yl-4-ethoxy-1-methoxy-3-methylnaphthalene (106.0 mg, 0.40
mmol), dissolved in THF (0.5 mL), were used in the cross-coupling
reaction following the procedure above with the exception that pen-
tane was used to crash out the zirconocene salts instead of hexanes.
The reaction was allowed to stir at r.t. for 16 h. Chromatography of
the residue (1% Et2O–petroleum ether) afforded 118.5 mg of the ti-
tle compound 19 (84%) as a clear oil; Rf 0.39 (1% Et2O–petroleum
ether).
MS (EI): m/z (%) = 329 (6, M – 57), 247 (17), 233 (50), 159 (19),
143 (58), 77 (100), 55 (33).
HRMS (EI): m/z calcd for C21H33F3OSi, M+ 329.1550; found
329.1549.
Triisopropyl{[(E)-7-(3-methoxyphenyl)-5-methylhept-5-enyl]-
oxy}silane (16)
TIPS-protected hex-5-yn-1-ol (190.6 L, 254 mg, 1 mmol), Me3Al
(1.50 mL, 3 mmol, 2 M in hexanes), Cp2ZrCl2 (146 mg, 0.5 mmol),
and ClCH2CH2Cl (1 mL) were used in the carboalumination follow-
ing the procedure above with the exception that the carboalumina-
tion was allowed to stir at r.t. for 3 h. Ni/C (67.3 mg, 0.04 mmol),
Ph3P (21 mg, 0.08 mmol), BuLi (40 L, 0.08 mmol, 2.45M), THF
(1 mL), and 3-methoxybenzyl chloride (116 L, 125 mg, 0.8 mmol)
were used in the cross coupling reaction following the procedure
above. The reaction was allowed to stir at r.t. for 13 h. Chromatog-
raphy of the residue on silica gel using hexanes afforded 234 mg of
the title compound 17 (78%) as a clear oil; Rf 0.11 (hexanes).
IR (neat): 2927, 2856, 1591, 1347, 1063 cm–1.
1H NMR (400 MHz, CDCl3): = 8.08–8.03 (m, 2 H), 7.49–7.43 (m,
2 H), 5.10 (tq, J = 1.2, 6.4, 1 H), 4.00 (q, J = 6.8 Hz, 2 H), 3.89 (s,
3 H), 3.58 (dd, J = 0.8, 6.2 Hz, 2 H), 2.39 (s, 3 H), 1.99 (t, J = 7.6
Hz, 2 H), 1.82 (d, J = 0.8 Hz, 3 H), 1.54 (t, J = 7.2 Hz, 3 H), 1.42–
1.35 (m, 2 H), 1.30–1.20 (m, 7 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): = 150.15, 149.07, 136.25, 131.29,
127.82, 127.59, 127.17, 125.54, 125.35, 122.91, 122.62, 122.23,
70.68, 61.52, 39.85, 31.96, 29.18, 28.10, 26.66, 22.87, 16.51, 16.12,
14.30, 12.64.
IR (neat): 2941, 1600, 1464, 1257, 1106, 909, 734 cm–1.
1H NMR (400 MHz, CDCl3): = 7.24–7.16 (m, 1 H), 6.82–6.71 (m,
3 H), 5.35 (tq, J = 1.2, 7.1 Hz, 1 H), 3.69 (t, J = 6.1 Hz, 2 H), 3.36
(d, J = 6.8 Hz, 2 H), 2.07 (t, J = 6.5 Hz, 2 H), 1.72 (s, 3 H), 1.63–
1.44 (m, 4 H), 1.08–1.07 (m, 21 H).
13C NMR (100 MHz, CDCl3): = 159.84, 143.69, 136.75, 129.44,
122.97, 120.94, 114.21, 111.17, 63.53, 55.30, 39.66, 34.41, 32.83,
24.29, 18.26, 16.20, 12.23.
MS (EI): m/z (%) = 354 (100, M+), 325 (17), 213 (45), 201 (18), 198
(16), 187 (10), 71 (12), 57 (17), 55 (10), 43 (25).
HRMS (EI): m/z calcd C24H34O2 354.2559; found 354.2547.
MS (EI): m/z (%) = 347 (100, M – 43), 131 (12), 121 (21), 103 (16),
75 (19), 61 (12).
HRMS (EI): m/z calcd for C24H42O2Si, M+ 347.2412; found
347.2412.
4-[(E)-7-{[tert-Butyl(dimethyl)silyl]oxy}-3-methylhept-2-enyl]-
thiazole (5)
In a 10 mL round bottom flask was added 4-chloromethylthiazole
hydrochloride (184 mg, 1 mmol), CH2Cl2 (2 mL), and Et3N (1 mL).
This mixture was allowed to stir for 15 min to generate the free
amine. The mixture was extracted with Et2O and filtered. The or-
Synthesis 2002, No. 14, 2110–2116 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cross-Couplings with Heterogeneous Ni/C Catalyst
2115
ganic layer was concentrated in vacuo and azeotropically dried with
toluene (3 ). TBDMS-protected hex-5-yn-1-ol (297 L, 212 mg, 1
mmol), Me3Al (1.50 mL, 3 mmol, 2 M in hexanes), Cp2ZrCl2 (146
mg, 0.5 mmol), and ClCH2CH2Cl (1 mL) were used in the carboalu-
mination following the procedure above with the exception that the
carboalumination was allowed to stir at r.t. for 5 h. Ni/C (67.3 mg,
0.04 mmol), Ph3P (21 mg, 0.08 mmol), BuLi (30 L, 0.08 mmol,
2.45M), THF (1 mL), and 4-chloromethylthiazole (4; 106 mg, 0.8
mmol) were used in the cross-coupling reaction following the pro-
cedure above, with the exception that the reaction was allowed to
stir at r.t. for 17 h and the quench was performed with H2O instead
of 1 M HCl. Chromatography of the residue (EtOAc–petroleum
ether, 2:1) afforded 217 mg of the title compound 5 (83%) as a clear
oil; Rf 0.41 (EtOAc–petroleum ether, 2:1).
MS (EI): m/z (%) = 220 (21), 135 (66), 122 (100), 109 (68).
HRMS (EI): m/z calcd for C15H21F, M+ 220.1635; found 220.1627.
Toluene-4-sulfonic Acid 2-(3,7,11,15,19,23,27,31,35,39-Decame-
thyltetraconta-2,6,10,14,18,22,26,-30,34,38-decaenyl)-5,6-dime-
thoxy-3-methylphenyl Ester (9)
The alkyne 3 (200 mg, 0.31 mmol) dissolved in ClCH2CH2Cl (0.25
mL), Me3Al (0.31 mL, 0.61 mmol, 2 M in hexanes), Cp2ZrCl2 (45
mg, 0.15 mmol), and ClCH2CH2Cl (0.3 mL) were used in the car-
boalumination following the procedure above with the exception
that the carboalumination was allowed to stir at r.t. for 5 h. Ni/C
(25.7 mg, 0.017 mmol), Ph3P (8.9 mg, 0.034 mmol), BuLi (10 L,
0.034 mmol, 2.45 M), THF (0.9 mL), and the tosylated benzyl chlo-
ride 1 (90.8 mg, 0.25 mmol), dissolved in THF (0.4 mL), were used
in the cross coupling reaction following the procedure above with
the exception that pentane was used to crash out the zirconocene
salts instead of hexanes. The reaction was allowed to stir at r.t. for
12 h. Chromatography of the residue (5% CH2Cl2–petroleum ether)
afforded 208.1 mg of the title compound 10 (85%) as a clear oil;
Rf 0.28 (5% CH2Cl2–petroleum ether).
IR (neat): 3073, 2930, 2858, 1649, 72, 1462, 1388, 1361, 1255,
1105, 836, 775 cm–1.
1H NMR (400 MHz, CD3CN): =9.57–9.56 (m, 1 H), 7.71–7.50
(m, 1 H), 5.43 (tq, J = 1.2, 3.7 Hz, 1 H), 4.68 (d, J = 10.1 Hz, 2 H),
3.62 (t, J = 6.1 Hz, 2 H), 2.03 (t, J = 6.1 Hz, 2 H), 1.70 (s, 3 H),
1.51–1.43 (m, 4 H), 0.89 (s, 9 H), 0.04 (s, 6 H).
IR (neat): 2963, 2919, 2853, 1741, 1500, 1449, 1372, 1177, 1115,
760 cm–1.
13C NMR (100 MHz, CD3CN): = 147.19, 110.42, 63.63, 38.13,
33.19, 26.34, 24.60, 22.44, -5.07.
MS (EI): m/z (%) = 325 (9, M+), 270 (10), 269 (20), 268 (100), 262
(88), 183 (66), 152 (17), 86 (12) 51 (13).
HRMS (EI): m/z calcd for C17H31NOSSi, M+ 325.1892; found
1H NMR (400 MHz, CDCl3): = 7.94 (d, J = 8.4 Hz, 2 H), 7.34 (d,
J = 8.4 Hz, 2 H), 6.65 (s, 1 H), 5.12 (m, 9 H), 5.02 (t, J = 7.2 Hz, 1
H), 3.82 (s, 3 H), 3.48 (s, 3 H), 3.32 (d, J = 6.4 Hz, 2 H), 2.46 (s, 3
H), 2.25 (s, 3 H), 2.07 (m, 18 H), 1.99 (m, 18 H), 1.69 (s, 6 H), 1.61
(s, 21 H), 1.60 (s, 3 H), 1.58 (s, 3 H).
325.1896.
13C NMR (100 MHz, CDCl3): = 151.05, 144.71, 142.51, 135.69,
135.21, 135.12, 135.08, 132.95, 131.45, 129.56, 128.42, 127.26,
124.59, 124.43, 124.31, 121.99, 113.15, 60.64, 56.20, 39.94, 39.92,
39.87, 26.95, 26.90, 26.79, 26.58, 25.91, 21.91, 19.97, 17.88, 16.42,
16.23.
1-Fluoro-4-[(E)-non-2-enyl]benzene (8)
To a 10 mL round-bottom flask under argon was added Schwartz’s
reagent Cp2Zr(H)Cl (188 mg, 95%, 0.70 mmol), THF (2 mL), and
oct-1-yne (103 L, 0.70 mmol). The mixture was stirred at r.t. for
30 min, after which time the hydrozirconation was complete (as de-
termined by TLC). The mixture was cooled to 0 °C, and diethylalu-
minum chloride (88 L, 0.70 mmol) was added dropwise and
allowed to stir for 1 h at 0 °C and 2 h at r.t. After the transmetalation
was complete, the THF was removed in vacuo and freshly distilled
hexanes (2 mL) were added and then also removed in vacuo. Addi-
tional hexanes (5 mL) were then added to the flask so as to precipi-
tate the zirconium salts. The alane in hexanes was then transferred
to a second flask via cannula (with great care taken to avoid con-
tamination by the zirconium salts), and the hexanes were removed
in vacuo. The yellow hexanes solution was concentrated under re-
duced pressure and the residue dissolved in THF (1.5 mL). To a 10
mL round bottom flask was added Ni/C (32 mg, 0.02 mmol) and
Ph3P (10.5 mg, 0.04 mmol) under argon at r.t. THF (0.5 mL) was
added followed by BuLi (15 L, 2.55 M in hexanes, 0.04 mmol).
The solution was allowed to stir at r.t. for 5 min. The alane was then
transferred via cannula to the Ni/C catalyst at r.t. 4-Fluorobenzyl
chloride (6; 48 L, 0.40 mmol) was added at r.t., and the cross-coup-
ling reaction was followed by GC analysis. After 16 h, the reaction
was complete and the mixture was diluted with Et2O (10 mL) and
quenched at 0 °C by carefully adding 1 M HCl dropwise (3 mL).
The mixture was filtered and the combined organic layers were
dried (Na2SO4) and concentrated in vacuo. Chromatography of the
residue on silica gel with pentane afforded 78 mg of the title com-
pound (88%) as a clear oil; Rf 0.60 (pentane).
MS (FAB): m/z (%) = 1004 (M+), 355 (17), 219 (45), 181 (100).
HRMS (FAB): m/z calcd C66H98NaO5S 1025.7032; found
1025.7077.
1-Fluoro-4-[(E)-3-methylnon-2-enyl]benzene (11)
Ni/C Re-use Experiment with Regeneration by BuLi (Scheme 6): Ni/
C was reclaimed by filtration of a prior, acid quenched reaction. It
was collected on a filter paper, washed with Et2O, azeotropically
dried with toluene (3 1 mL), and finally heated at 100 °C under
high vacuum for 6 h. The Ni/C was then used according to the gen-
eral procedure detailed above with the following reagents: oct-1-
yne (150 L, 110 mg, 1 mmol), Me3Al (0.75 mL, 1.5 mmol, 2 M in
hexanes), Cp2ZrCl2 (73 mg, 0.25 mmol), and ClCH2CH2Cl (1 mL)
were used in the carboalumination following the procedure above.
Ni/C (67.5 mg, 0.04 mmol), Ph3P (21 mg, 0.08 mmol), BuLi (33 L,
0.08 mmol, 2.45 M), THF (1 mL), and 4-fluorobenzyl chloride (6;
100 L, 116 mg, 0.8 mmol) were used in the cross-coupling reaction
following the procedure above. The reaction was allowed to stir at
r.t. for 4 h. Standard workup followed by chromatography of the
residue on silica gel with pentane afforded 172.1 mg of the title
compound (92%) as a clear oil; Rf 0.71 (pentane).
IR (neat): 2959, 2927, 2856, 1642, 1508, 1223 cm–1.
1H NMR (400 MHz, CDCl3): =7.20–7.10 (m, 2 H), 7.05–6.90 (m,
2 H), 5.32 (tq, J = 1.2, 7.4 Hz, 1 H), 3.34 (d, J = 7.2 Hz, 2 H), 2.04
(t, J = 7.2 Hz, 2 H), 1.71 (s, 3 H), 1.50–1.40 (m, 2 H), 1.35–1.20 (m,
6 H), 0.9 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): = 162.62, 160.20, 137.64, 137.10,
129.82, 129.74, 122.79, 115.31, 115.10, 39.90, 33.55, 31.99, 29.21,
28.12, 22.89, 16.26, 14.32.
IR (neat): 2926, 2855, 1601, 1508, 1466, 1222, 1156, 1092, 967,
822 cm–1.
1H NMR (400 MHz, CDCl3): = 7.15–7.12 (m, 2 H), 7.00–6.94 (m,
2 H), 5.57–5.46 (m, 2 H), 3.30 (d, J = 4.9 Hz, 2 H), 1.44–1.30 (m,
10 H), 0.89 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): = 132.58, 130.03, 129.95, 128.74,
115.32, 115.11, 38.41, 32.70, 31.92, 29.62, 29.07, 22.85, 22.56,
14.31.
MS (EI): m/z (%) = 234 (17, M+), 149 (100), 122 (22), 109 (45).
HRMS (EI): m/z calcd for C16H23F, M+ 234.1784, found 234.1782.
Synthesis 2002, No. 14, 2110–2116 ISSN 0039-7881 © Thieme Stuttgart · New York

2116
B. H. Lipshutz et al.
PAPER
1-Fluoro-4-[(E)-3-methylnon-2-enyl]benzene (11)
petroleum ether). (See above experimental (Table 1, entry 2) for IR,
1H, NMR, 13C NMR, and MS data).
Ni/C Re-use Experiments Without Regeneration; (Scheme 7): Un-
like the general procedure, these reactions were conducted in a cen-
trifuge tube so as to be able to settle the Ni/C once the first reaction
was complete. Oct-1-yne (150 L, 110 mg, 1 mmol), Me3Al (0.75
mL, 1.5 mmol, 2 M in hexanes), Cp2ZrCl2 (73 mg, 0.25 mmol), and
ClCH2CH2Cl (1 mL) were used in the carboalumination following
the procedure above. Ni/C (67.5 mg, 0.04 mmol), Ph3P (21 mg, 0.08
mmol), BuLi (33 L, 0.08 mmol, 2.45 M), THF (1 mL), and
4-fluorobenzyl chloride (6; 100 L, 116 mg, 0.8 mmol) were used
in the cross-coupling reaction following the procedure above. The
reaction was allowed to stir at r.t. for 4 h. Upon completion of the
reaction, the reaction vessel was placed in the centrifuge for 10 min.
After that time, the solution was transferred via syringe to a round
bottom flask containing aq sat. NH4Cl solution. To the reaction tube
was added anhyd THF (1 mL) and the mixture was stirred for 5 min.
The reaction vessel was again placed in the centrifuge for 10 min.
The liquid layer was again removed via syringe and added to the
same round bottom flask. The second reaction was then started.
Upon typical aqueous acidic quench, column chromatography of
the residue on silica gel with pentane afforded 175.6 mg of the title
compound (94%) as a clear oil. (See above experimental for IR, 1H
NMR, 13C NMR, and MS data.)
Acknowledgement
Financial support provided by the NIH (GM 40287) is warmly ack-
nowledged with thanks. We are grateful to Mr. Paul Forster (UCSB
MRL) for assisting with the ICP analyses.
References
(1) Lipshutz, B. H.; Mollard, P.; Pfeiffer, S. S.; Chrisman, W.,
submitted.
(2) For a related study using Ni(0) under homogeneous
conditions, see: (a) Lipshutz, B. H.; Kim, S.-K.; Mollard, P.;
Stevens, K. L. Tetrahedron 1998, 54, 6999. (b) Lipshutz, B.
H.; Bulow, G.; Stevens, K. L.; Lowe, R. Tetrahedron 1996,
52, 7265.
(3) Lipshutz, B. H. Adv. Synth. Catal. 2001, 343, 313.
(4) (a) Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc. 1999,
121, 5819. (b) Lipshutz, B. H.; Tomioka, T.; Blomgren, P.
A.; Sclafani, J. A. Inorg. Chim. Acta 1999, 296, 164.
(c) Lipshutz, B. H.; Sclafani, J. A.; Blomgren, P. A.
Tetrahedron 2000, 56, 2139. (d) Lipshutz, B. H.; Ueda, H.
Angew. Chem., Int. Ed. 2000, 39, 4492; Angew. Chem. 2000,
112, 4666. (e) Lipshutz, B. H.; Tomioka, T.; Sato, K. Synlett
2001, 970.
(5) (a) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978,
100, 2252. (b) Negishi, E.; Van Horn, D. E.; Yoshida, T. J.
Am. Chem. Soc. 1985, 107, 6639. (c) Matsushita, H.;
Negishi, E. Org. Synth. 1984, 63, 31. (d) Negishi, E. Pure
Appl. Chem. 1981, 53, 2333.
(6) Lipshutz, B. H.; Tasler, S. Adv. Synth. Catal. 2001, 343, 327.
(7) Inductively Coupled Plasma Mass Spectrometry; Montaser,
A., Ed.; Wiley-VCH: New York, 1998.
tert-Butyl{[(E)-7-(2-chlorophenyl)-5-methylhept-5-
enyl]oxy}dimethylsilane (13)
Ni/C Re-use, Second experiment, Without Regeneration by BuLi: In
the same reaction vessel containing the previously used Ni/C was
added TBDMS protected hex-5-yn-1-ol (184 mg, 1 mmol), Me3Al
(1.5 mL, 3.0 mmol, 2 M in hexanes), Cp2ZrCl2 (146 mg, 0.50
mmol), and ClCH2CH2Cl (1 mL) were used in the carboalumination
following the procedure above with the exception that the carboalu-
mination was allowed to stir at r.t. for 6 h. Ph3P (21 mg, 0.08 mmol),
THF (1 mL), and 1-chloro-2-(chloromethyl)benzene (12; 100 L,
129 mg, 0.8 mmol) were used in the cross-coupling reaction follow-
ing the procedure above. The reaction was allowed to stir at r.t. for
16 h. Upon typical aqueous acidic quench, chromatography of the
residue on silica gel with 2% CH2Cl2–petroleum ether afforded 248
mg of the title compound (88%) as a clear oil; Rf 0.25 (2% CH2Cl2–
(8) Lipshutz, B. H.; Tasler, S.; Chrisman, W.; Spliethoff, B.;
Tesche, B. J. Org. Chem. in press.
Synthesis 2002, No. 14, 2110–2116 ISSN 0039-7881 © Thieme Stuttgart · New York